Cotranslational folding in ab initio protein structure prediction and applications in de novo design;

从头开始蛋白质结构预测中的共翻译折叠及其在从头设计中的应用；

• 批准号: 2105285
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2105285
• 关键词: Cotranslational; folding; ab; initio; protein

PROTACs (proteolysis-targeting chimera) are heterobifunctional molecules. They function by binding to a protein of interest (POI) and an E3 ligase. Bringing the POI into close proximity with the E3 ligase leads to polyubiquitination, which marks the POI for degradation by the proteosome. This mechanism of action makes PROTAC molecules exciting candidates for therapies which require long-term downregulation of a specific protein [1] [2].Many PROTAC molecules are derived from small molecules with known protein binding properties. A frequent approach is to tether a known small molecule E3 ligase binder to a different small molecule that is known to bind the protein of interest via a linker region (usually polyethylene glycol, or PEG).This project will be concerned with a smaller class of molecules known as IMIDs (immunomodulatory imide drugs). Members of this drug class include thalidomide, lenalidomide, and pomalidomide. Although not structurally similar to the more traditional chimeric PROTAC molecules, it is now known that IMIDs exhibit their pharmaceutical effects via a PROTAC-like mechanism. The imide component of the molecule - acting as an analogue of the biomolecule uridine - binds to the E3 ligase protein cereblon in a triple tryptophan hydrophobic pocket. The phthalimide half of the molecule, protruding out from the cereblon E3 ligase protein, alters the surface topology of cereblonFigure 1 PROTACS mechanism of action: In the absence of the protac molecule, the target protein is not degraded; in the presence of the protac, the target protein is linked to an E3 ligase, which marks it for degradation via polyubiquitination [13]such that it will now bind with a variety of other proteins, which all become marked for degradation via the aforementioned route.Work by GSK has explored the conserved features found amongst these target proteins in nature. Although diverse in overall shape, these proteins all share a small motif which binds to the IMID/cereblon complex. This motif is not conserved in terms of primary sequence, but is structurally analogous in each case. There is also a conserved glycine residue, which accommodates binding of the phthalimde motif of the IMID. Any residue other than glycine in this position would be too sterically crowded.Tests carried out by GSK have shown that this shared motif, hereafter referred to as a degron, can be added to a protein and used as a tag for degradation in the presence of an IMID drug. This approach has been named IPID (IMID Proximity Induced Degradation). Assays involving recombinant GFP-degron hybrids with variable GlySer linker lengths demonstrate the proof of concept.A current research goal at GSK is to explore the possibility of including this switch in CAR-T cell therapy (chimeric antigen receptor T cell therapy), a form of immunotherapy where T cells are modified to recognise and destroy the patient's own cancer cells. The protein through which this is achieved comprises of the scFv region of a monoclonal antibody, fused to a transmembrane domain

protac（促蛋白水解靶向嵌合体）是异常分子。它们通过与感兴趣的蛋白质（POI）和E3连接酶结合来起作用。使POI与E3连接酶非常接近，导致多泛素化，这标志着蛋白质体降解的POI。这种作用机制使Protac分子令人兴奋的候选疗法，这些疗法需要长期下调特定的蛋白质[1] [2]。许多Protac分子来自具有已知蛋白质结合特性的小分子。一种常见的方法是将已知的小分子E3连接酶粘合剂绑定到一个不同的小分子上，该分子已知可以通过接头区域（通常是聚乙烯乙二醇或PEG）结合感兴趣的蛋白质。该项目将与称为imids的较小分子有关（免疫管状Imide Imide Imide药物）。该药物类别的成员包括沙利度胺，莱纳利度胺和Pomalidomide。尽管在结构上与更传统的嵌合Protac分子不同，但现在众所周知，IMIDS通过Protac样机制表现出其药物作用。分子的酰亚胺成分 - 作用于生物分子尿苷的类似物 - 与三色色氨酸疏水口袋中的E3连接酶蛋白小脑结合。分子的邻苯二甲胺一半从小脑E3连接酶蛋白伸出，改变了典型的表面拓扑1 protac的作用机制：在缺乏protac分子的情况下，靶蛋白不会降解；在存在Protac的情况下，靶蛋白与E3连接酶有关，它标记了通过多泛素化[13]进行降解[13]，因此它将与其他各种蛋白质结合，这一切都通过上述路线进行了降解。GSK探索了在这些目标蛋白质中发现的保守特征。尽管整体形状各不相同，但这些蛋白质都共享一个小基序，与IMID/Cereblon络合物结合。该基序不是基本序列的保守，但在每种情况下在结构上都是类似的。还有一个保守的甘氨酸残基，可容纳IMID的邻苯二甲层基序的结合。在该位置，除甘氨酸以外的任何残留物都会太拥挤。GSK进行的测试表明，这种共享图案（以下称为Degron）可以添加到蛋白质中，并用作在IMID药物存在下降解的标签。该方法已命名为iPID（IMID接近性降低）。涉及重组GFP-Degron混合体具有可变的Glyser连接器长度的测定证明了概念证明。GSK的当前研究目标是探索将这种转换纳入CAR-T细胞疗法中的可能性（嵌合抗原受体T细胞疗法）（嵌合抗原受体T细胞疗法），一种T细胞的形式，其中T细胞改善了T细胞以识别和破坏患者的癌症。实现的蛋白质包括单克隆抗体的SCFV区域，融合到跨膜结构域